JPH04327525A - Sustained release medicine-containing ceramic porous substance - Google Patents

Abstract

PURPOSE:To obtain a sustained release medicine-containing ceramic porous substance capable of sustaining a medicine for a long period and preventing side effects due to concentrated elution of the medicine by applying a biodegradable substrate containing the medicine, dispersed and held therein to the inner wall surfaces in pores and the outside surface of a ceramic porous substance. CONSTITUTION:A sustained release medicine-containing ceramic porous substance is obtained by applying a biodegradable substrate containing and holding a dispersed medicine therein and further containing at least one selected from chitin and its derivative or collagen to the inner wall surfaces of pores and the outside surface of a ceramic porous substance composed of calcium phosphate-based ceramics, alumina, zirconia, etc. Calcium phosphate-based ceramics excellent in biocompatibility, etc., are preferred as the aforementioned ceramics and tricalcium phosphate and hydroxyapatite at 1.4-1.7 atomic ratio (Ca/P) are especially preferred in aspect of rapid production of newly formed bones. The porosity of the ceramic porous substance is preferably 30-95% and the average pore diameter is preferably within the range of 10-300mum.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention is capable of controlled and sustained release of drugs, which are used for artificial bone to be replaced at the site where bone has been removed, for the treatment of osteomyelitis, malignant tumors, etc., and for the prevention of infection. This invention relates to a ceramic porous body containing a drug.

0002

BACKGROUND OF THE INVENTION When administering a drug to localized inflammation, tumors, etc., the efficacy of the drug is greatly affected by the local convection time of the drug. In general, living organisms have the ability to rapidly eliminate such drugs, so they are usually absorbed and refluxed into the bloodstream immediately after administration and excreted through the liver and kidneys.

[0003] In order to maintain the effects of drugs over a long period of time against this rapid excretion effect, it is necessary to devise a method for administering drugs in a sustained release manner. For this purpose,
Porous ceramics impregnated with a drug solution in which the pores of the ceramic body are impregnated with a drug (Japanese Patent Application Laid-open No. 59-101145), Ceramic small granules for drug administration in which the small pores of the granules contain a drug (Japanese Patent Publication No. 1988-101145) -6522), a calcium phosphate filler containing an antibiotic in the small pores and forming a calcium phosphate layer around the pores (JP-A-60-106)
459).

0004

[Problems with the Prior Art] All of the above-mentioned drug-containing ceramic bodies merely retain the drug as is in the pores of the ceramic, so that the medicinal efficacy is not necessarily maintained for a long period of time.

[0005]

[Means for Solving the Problems] In order to solve the above-mentioned problems, the present invention is not limited to a mere drug-impregnated container, but a drug-retaining container selected from chitin, its derivatives, or collagen, which has excellent long-lasting medicinal effects. A porous ceramic body containing a sustained-release drug is provided, in which a biodegradable substrate containing at least one type of substrate is attached to the inner wall surface and the outer surface of the pores of the porous ceramic body.

[0006]

【Example】

Example 1 Hydroxyapatite was made into a slurry using a ball mill,
After being impregnated with approximately 1 cm 3 of #30 urethane foam, it was fired at 1300° C. to produce two ceramic porous bodies made of hydroxyapatite with a porosity of 90% and an average pore diameter of 300 μm. Next, 5 g of chitin and 1 g of collagen were dissolved in 50 ml of a hydrochloric acid solution with a pH of 3.0, and 2 g of kanamycin, an antibiotic, was mixed with this composite solution. One of the above-mentioned hydroxyapatite porous bodies was immersed in this solution, defoamed under reduced pressure, dried, and then washed with water to remove excess hydrochloric acid. The sustained-release drug-containing ceramic of the present invention contains a chitin/collagen biodegradable substrate 2 in which chitin/collagen is dispersed and adhered to the inner and outer surfaces of the pores 4 of the hydroxyapatite porous body 3. A porous body 5 was produced.

[0007]

[Table 1]

Table 1 shows the results of evaluating the physical properties of one porous ceramic body according to the present invention and the porous ceramic body not containing a biodegradable base material prepared in this way. The compressive strength was measured using a universal testing machine.

Next, the conventional drug-containing porous ceramic material in which kanamycin was contained in a slurry state in the ceramic porous material and the sustained-release drug-containing porous ceramic material according to the present invention were immersed in 50 ml of a phosphate buffer solution. , 37
The cumulative elution rate of kamycin was examined over time using a liquid chromatograph after it was released slowly in a temperature incubator. The results are shown in Table 2. In addition, kanamycin is contained in conventional drug-containing porous ceramic materials after pulverizing kanamycin to several micrometers.
In order to make it viscous, sterilized water was added to form a slurry, and the ceramic porous body was impregnated with the slurry, which was then dried.

0010

[Table 2]

FIG. 2 is a graph showing the results of Table 2, and as is clear from FIG. 2, it took 8 days in the case where kanamycin was simply added, whereas in the case of the chitin-collagen biological body in which kanamycin was dispersed and maintained. The sustained-release drug-impregnated ceramic porous body of the present invention, which contains a degradable base material attached to the pore surface of the porous body, is about 32 days, indicating that the present invention is stable for a longer period of time than the conventional one. It can be seen that the drug was eluted.

By the way, as the material constituting the ceramic porous body, materials that are not harmful to living organisms, such as calcium phosphate ceramics, alumina, and zirconia, are used. Among these, calcium phosphate ceramics are optimal because they produce good new bone and have excellent biocompatibility.

Calcium phosphate compounds include CaHPO
4-2 H2O (brushite), CaH
PO4 (monetite), Ca2P2O
7 (calcium pyrophosphate), Ca3 (PO
4) 2 (Tricalcium phosphate), Ca
5 (PO4) 3 (OH) (hydroxyapatite), etc., and these compounds can be used alone or in combination with 2
It can be used as a mixture of more than one species. Among these, tricalcium phosphate, hydroxyapatite, and the like having an atomic ratio of Ca/P in the range of 1.4 to 1.7 are preferred because they generate new bone faster than other calcium phosphate compounds.

[0014] The ceramic porous body has an arbitrary porosity and average pore diameter that allow the biodegradable base material in which the drug is dispersed and held to be attached and contained on the surface of the pores. In general, drug carriers used for the same purpose as the present invention usually have a porosity =
10 to 98%, average pore size = 1 to 500 μm.However, in the ceramic porous body that is a component of the present invention, if the porosity is 30% or less or the average pore size is 10 μm or less, the biodegradable group holding the drug dispersedly It is difficult or impossible to produce a material that does not contain enough material and has a porosity of 95% or more. Furthermore, if the average pore diameter is 300 μm or more, the duration of the medicinal effect maintained in the dispersed state will be shortened, and the effect will not be sufficiently enhanced. Therefore, the porosity of the ceramic porous body of the present invention is 30 to 95%, and the average pore diameter is 10 to 95%.
300 μm is preferred.

[0015] Various known methods can be used for producing the ceramic porous body. For example, a porous body with a porosity of up to about 50% can be produced by mixing ceramic powder with an organic substance, molding it, and firing it. or,
The porosity can be increased to about 95% by immersing a sponge made of a polymeric material in a slurry mixed with ceramic powder and firing, which is the same method as in this example.

Next, chitin, which is a biodegradable base material for dispersing and retaining drugs, is N, which is obtained by treating crustaceans, middle insects, etc. with hydrochloric acid and sodium hydroxide treatment to separate and purify proteins and inorganic substances. -Acetyl-D glucosamine has β-1,4 bonds, and chitosan is its deacetylated product. Chemical formula 1 shows the general formula of chitin and chitosan.

[0017]

[Chemical formula 1]

Biodegradable substrates for holding drugs include chitin, chitosan, etherified products, esterified products,
Carboxyl methylated products and other derivatives thereof, as well as collagen, are used. Of these, collagen is the main protein that makes up connective tissues such as bones and skin of animals, and its molecular weight is approximately 100,000 and consists of three polypeptide chains. Collagen gathers together to form a unique helical structure. A non-helical peptide chain (telopeptide) is attached to both ends of this molecule, and it is known that the antigenicity of collagen is due to the presence of this telopeptide. Collagen, which serves as a biodegradable base material used to hold drugs, is produced by treating cowhide etc. with enzymes or alkali, which are known methods, and is substantially free of telopeptide chains, that is, has no antigenicity. Atelocollagen that does not have is used. Furthermore, gelatin, which is a denatured product of collagen, can also be used as a biodegradable base material for holding drugs.

The type, concentration, etc. of the biodegradable substrate used to hold the drug are selected depending on the purpose and use.

[0020] The drugs that are retained are those that require maintenance of their efficacy over a long period of time. Examples include antibiotics, anticancer drugs, protein drugs, bone morphogenetic factors, and the like. Specifically, as the antibiotic, penicillins, cephalosporins, kanamycin, tetracycline, actinomycin, etc. are used. As anticancer drugs, carcinophilin, sarcomycin, pleomycin, cyclofofamide, etc. are used. As the osteogenic factor, bone morphological protein and the like are used. The method for retaining the above-mentioned drugs on a biodegradable substrate is as follows:
After dissolving the biodegradable base material used to hold the drug, chitin, chitosan, collagen, etc. in a solvent such as formic acid, hydrochloric acid, or acetic acid, dispersing the drug, and sterilizing the porous ceramic body, By immersing the above porous body in a solution containing the above drug dispersed therein and reducing the pressure using a vacuum pump, the air inside the pores is removed, and the biodegradable base material holding the drug is released into the pores of the porous body. Adheres to internal surfaces. This is dried at room temperature or freeze-dried to obtain a sustained-release drug-containing ceramic porous body in which the biodegradable base material holding the drug adheres to the inner surface of the pores of the porous body.

On the other hand, a porous body obtained by impregnating a spongy organic continuous porous body with a slurry in which ceramic powder is mixed and firing it has low strength. However, since the biodegradable base material holding the drug in this porous body coats the outer surface of the porous body and the inner surface of the pores, the strength is increased. Note that the amount of the drug contained varies depending on the size, shape, purpose of use, etc. of the porous ceramic body, and is determined depending on the case to which it is applied.

Example 2 100g of tricalcium phosphate was mixed with 50g of naphthalene, and the mixture was press-molded at 1200°C.
After firing, the mixture was classified to produce two ceramic porous bodies of α-tricalcium phosphate.

[0023] 4 g of chitosan was added to a formic acid solution with a pH of 4.0.
3 g of cisplatin, an anti-cancer agent, was dispersed in 0 ml of the solution. 30g of the above porous granules were immersed in this solution, defoamed under reduced pressure, and dried.The chitosan biodegradable base material with cisplatin dispersed therein was attached to the surface of the pores and α attached to external surface
A ceramic porous body containing a sustained release drug of tricalcium phosphate according to the present invention was prepared. Table 3 shows the physical properties of the porous α-tricalcium phosphate containing the biodegradable base material in which cisplastin is dispersed and held.

[0024]

[Table 3]

[0025] In parallel, the remaining one of the above ceramic porous bodies was soaked in 50 m of a phosphate buffer solution of pH 7.4.
The sustained-release drug-containing porous ceramic body of the present invention is prepared by preparing a conventional drug-containing porous ceramic body containing cisplastin by immersing it in water, and by making cisplastin dispersed and retained in the chitosan produced by the above-described method. Example 1 with the body
Table 4 shows the results of examining the cumulative elution rate of cisplastin over time.

[0026]

[Table 4]

Furthermore, a graph of the results of Table 4 is shown in FIG. As is clear from Table 4 and FIG. 3, the conventional drug-containing porous ceramic body loses sustained release properties after 10 days, and sustained drug efficacy cannot be expected. A stable elution trend was observed even after the passage of time, indicating that the drug was continuously elution.

Example 3 100 g of tricalcium phosphate was mixed with 40 g of paraffin wax and press-molded into 110 g of tricalcium phosphate.
After firing at 0℃, porosity 35%, average pore diameter 200 μm
Two ceramic porous bodies of β-tricalcium phosphate were prepared.

[0029] 2 g of chitosan was added to 50 m of a formic acid solution with a pH of 5.
2 g of an antibiotic, tetracycline, was mixed with the solution dissolved in 1 liter of water. One of the ceramic porous bodies described above was immersed in this solution, and otherwise a sustained-release drug-containing ceramic porous body of the present invention was produced in the same manner as in Example 1. Further, using the remaining one of the above ceramic porous bodies, a conventional drug-containing ceramic porous body containing tetracycline was prepared using the same method as in Example 1. The amount of tetracycline in the former was 45 mg per cm 3 of the porous material, and the amount in the latter was 50 mg, but the cumulative elution rate of tetracycline was examined over time in the same manner as in Example 1. The results are shown in Figure 4.

As is clear from FIG. 4, it can be seen that the sustained-release drug-containing ceramic porous body of the present invention exhibited sustained drug release properties even after 60 days.

Example 4 50 g of carbon was added to 100 g of hydroxyapatide.
After baking the mixture at 1100° C., two ceramic porous bodies having a porosity of 50% and an average pore diameter of 40 μm were prepared.

[0032] 2 g of chitosan and 1 g of gelatin at pH 5.0
was dissolved in 50 ml of acetic acid solution, and 2 g of pleomycin, an anticancer agent, was mixed with this solution. Others, Example 1
One sustained-release drug-containing ceramic porous body of the present invention was prepared in the same manner as in Example 1, and one conventional drug-containing porous ceramic body containing pleomycin was prepared in the same manner as in Example 1. The pleomycin content of the former is 22 mg per cm 3 of the porous material, and the latter is 22 mg per cm 3 of the porous material.
The total dissolution rate was examined over time in the same manner as in Example 1 using these samples. The results are shown in Figure 5.

As is clear from FIG. 5, the cumulative dissolution rate of the sustained-release drug-containing ceramic porous body of the present invention is approximately 60% even after 40 days, indicating sustained drug release properties. .

Comparative Example: Hydroxyapatite was made into a slurry using a ball mill.
After being impregnated with approximately 1 cm 3 of #10 urethane foam, it was fired at 1300° C. to produce a ceramic porous body made of hydroxyapatite with a porosity of 97% and an average pore diameter of 350 μm. Next, 5 g of chitin and 1 g of collagen were dissolved in 50 ml of a hydrochloric acid solution with a pH of 3.0, and 2 g of kanamycin, an antibiotic, was mixed with this composite solution. In addition, a drug-containing ceramic porous body in which kanamycin was dispersed and retained in chitosan and had a kanamycin content of 12 mg per cm 3 of the porous body was prepared in the same manner as in Example 1. The cumulative elution rate of kanamycin was investigated over time. The results are shown in Figure 6.

As is clear from FIG. 6, this drug-containing ceramic porous material had a cumulative dissolution rate of 90% in about 15 days, which was hardly different from the several conventional drug-containing porous ceramic materials mentioned above. I couldn't.

As described above, chitin, chitosan and its derivatives, and collagen as biodegradable base materials are highly safe as biomaterials, and the present invention can be achieved by changing the concentration of these biodegradable base materials. With porous ceramics, it is possible to adjust and control the amount and time of sustained release of the drug. Furthermore, the calcium phosphate material that forms the framework of the porous ceramic has excellent affinity with bones and is optimal as a bone replacement material containing drugs such as antibiotics.

[0037]

Effects of the Invention: When the porous ceramic material of the present invention is applied to the affected area, it is possible to achieve stable sustained release of the drug over a long period of time, that is, to maintain the drug's efficacy for a long period of time, to prevent side effects caused by concentrated elution of the drug, and to ensure safety in vivo. Since highly durable materials are used for the aggregate and the drug holding material, there is no risk of adverse effects on the living body, and the psychological anxiety of the patient can be alleviated.

[Brief explanation of drawings]

FIG. 1 is a partially cutaway sectional view showing a porous ceramic body of the present invention.

FIG. 2 is a graph showing the results of Table 2.

FIG. 3 is a graph showing the results of Table 4.

FIG. 4 is a graph showing the results of Example 3.

FIG. 5 is a graph showing the results of Example 4.

FIG. 6 is a graph showing the results of a comparative example.

[Explanation of symbols]

1: Kanamycin 2: Chitin/collagen biodegradable base material 3: Porous material 4: Hole 5: Ceramic porous body of the present invention

Claims (1)

[Claims] A sustained-release drug-containing ceramic porous body comprising a biodegradable base material containing at least one selected from chitin, its derivatives, or collagen, in which a drug is dispersed and adhered to the inner wall surface and outer surface of the pores of the porous ceramic body.